Human and animal body metabolism uses oxygen and produces carbon dioxide. The required oxygen is received from the atmospheric air during respiration, in the course of which waste carbon dioxide is released. The gas exchange between the body and the environment takes place in the lung alveoli, where pulmonary blood capillaries are separated from the gas space in the lung in communication with the atmospheric air by only a thin membrane permeable for gases. The pulmonary blood flow passing through the alveoli equilibrates in gas partial pressure with the alveolar gas, resulting in blood oxygen uptake and carbon dioxide release. During each breath the alveolar blood gas concentration is changed as a result of the oxygen supplement and carbon dioxide removal. The blood transports the oxygen from the lungs to the sites of consumption and waste carbon dioxide from the sites of metabolism back to the lungs.
Blood flow rates through the lungs and perfusion pressure are regulated by the smooth muscle tension of the pulmonary capillaries. This regulation is mediated by endothelium derived nitric oxide. Insufficient local NO production increases smooth muscle tone. This results in pulmonary vasoconstriction and impaired blood flow or, alternatively, elevated pulmonary artery pressure. Pulmonary hypertension is present in various circumstances, such as pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, prenatal aspiration syndrome, hyaline membrane disease, acute pulmonary embolism, heparinprotamine reactions, sepsis, or hypoxia (including that which may occur during one-lung anesthesia), as well as those cases of chronic pulmonary vasoconstriction which have a reversible component, such may result from chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary embolism, idiopathic or primary pulmonary hypertension, or chronic hypoxia due to chronic obstructive lung disease.
U.S. Pat. No. 5,485,827 discloses a method using inhaled nitric oxide (NO) useful for preventing or reversing acute pulmonary vasoconstriction, such as that arising from the foregoing injuries. A method for using NO gas also to achieve bronchodilatation and thereby improve the distribution of other agents administered by inhalation is also disclosed.
A special advantage of inhaled NO as a pulmonary vasodilator is its selectivity. NO is rapidly bound with blood hemoglobin, thus the free NO needed for mediating the vasodilatation is available selectively for the smooth muscles of the pulmonary capillaries only, and even more specifically, for the pulmonary capillaries adjacent ventilated alveoli. The pulmonary blood for alveoli which are not ventilated form a pulmonary shunt flow, since the non-ventilated alveoli are rapidly equilibrated with the pulmonary artery blood gases and no further gas exchange will take place. The pulmonary blood flow not participating in the gas exchange is thus called shunt flow. One reason for using inhaled NO therapy is to reduce the alveolar-arterial oxygen partial pressure difference for better oxygenation. The mechanism for this is reduction of the shunt. Administration of NO to ventilated alveoli dilates the pulmonary capillaries carrying blood for gas exchange. Capillaries in communication with the non-ventilated alveoli are constricted due to the low NO concentration. This results in blood perfusion redistribution towards the ventilated lung areas. When the portion of the pulmonary perfusion participating in the blood flow increases, the arterial oxygen partial pressure will increase, improving oxygenation.
Despite this well known mechanism, the published research results of inhaled NO for improving oxygenation have been limited. Examples of studies of oxygenation improvements are e.g. Gerlach et al.: xe2x80x9cLong-term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndromexe2x80x9d, Intensive Care Med (1993) 19:443-449; Gerlach et al.: xe2x80x9cTime-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndromexe2x80x9d, Euro J. of Clinical Investigation (1993) 23: 449-502:, Benzing et al.: xe2x80x9cHypoxic pulmonary vasoconstriction in non-verlated lung areas contributes to diff ences in hemodynamic and gas exchange responses to inhalation of nitric oxidexe2x80x9d, Anesthesiology (1997) 86:1254-61. In all these, and other, published studies, NO has been administered to patients having a diagnosis of lung disease.
The NO delivery rate for improving oxygenation has both minimum and maximum limits making the oxygenation improvement clinically challenging. The loss of the oxygenation effect with increased doses is most likely traced back to the smooth muscle sensitivity. With increasing delivery, more NO diffuses to non- or poorly ventilated alveoli causing dilatation. This impairs the improvement in oxygenation seen prior to increasing the dose, as discussed by Gerlach in xe2x80x9cTime-course . . . xe2x80x9d The balance between improved and impaired gas exchange depends on lung status and is, therefore, individual for each patient. When the ventilation or lung performance is changing, most likely this balance is also affected.
Pulmonary shunt variation is very commonly present in healthy and sick lungs in various daily life and treatment conditions. Atelectasis, areas of the lung not participating in the gas exchange due to collapse of the alveoli, prevent normal oxygen delivery, and increases the pulmonary shunt. It has been pointed out that atelectasis is present during almost every anaesthesia (A. Strandberg et al: xe2x80x9cAtelectasis during anaesthesia and in the postoperative periodxe2x80x9d, Acta Anaesthesiol. Scand. (Feb. 1986) 30:2,154-8); L. Tokic et al: xe2x80x9cLung collapse and gas exchange during general anesthesia: effects of spontaneous breathing, muscle paralysis, and positive end expiratory pressurexe2x80x9d, Anesthesiology (Feb. 1997) 66:2, 157-67). In normal healthy subjects this atelectasis is not very significant due to the oxygenation reserve.
The severity of atelectasis will increase along with decrement of the oxygenation reserve. During artificial ventilation in anaesthesia and intensive care it is possible to increase the inhaled oxygen fraction and thereby increase the oxygenation reserve. In extensive collapse of lung, aeration with even 100% oxygen in the inhaled gases may not be sufficient. An example where the oxygenation reserve is endangered is horses experiencing anaesthesia in the unnatural supine position. The lungs, anatomically suited for the standing position, will be compressed by the body mass in the supine position. The lung volume can be reduced by as much as 50% and cause a pulmonary perfusion shunt of 20-50%. NO delivered to the inspired gas ca distribute the blood flow to ventilated areas and improve oxygenation.
Similar problems, which may in the worst case be chronic in nature, are encountered by humans having morbid obesity, i.e. twice the normal body weight, or 50 kg over the normal, or a body mass index over 40. In the supine position the lung functional residual capacity, FRC, is markedly reduced by the tissue mass restricting the lung volume. This may lead to impaired oxygenation and pulmonary shunt without any diagnosis of lung disease especially when sleeping when the lungs are squeezed by the body mass. Even worse, the diaphragm of obese people tends to assume a position which can be described as elevated when a person is standing, leading to a decrease in lung volume and increase in shunt. This may cause oxygenation problems even in normal daily life. The problem also occurs in anaesthesia or intensive care, and extends also to postoperative care where the restoration of normal pulmonary functions may take 4-5 hours (Brodsky: xe2x80x9cMorbid obesityxe2x80x9d, Current Anaesthesia and Critical Care (1998) 9:249-254).
The compression of the lungs by the mass exerted on it may cause alveolar collapse during the time in which expiration occurs. The collapsed alveoli will open during the course of an inspiration when the lung opening pressure increases. The lung opening pressure required to open the lung increases towards the lowermost lung regions where the presence of the compressing mass of an obese person also increases, and more lung volume will be recruited along the progress of the inspiration. In spontaneous breathing this opening pressure is an underpressure in pleural cavity generated by breathing muscles of which the diaphragm is the most important. In artificial ventilation the opening pressure is overpressure in the lung gas space generated by the ventilator. At the beginning of expiration the lung opening pressure is relieved and the emptying of the lungs starts. The lung regions opened last during inspiration will close first at the beginning of expiration. This lung collapse will continue upwards from the lowermost lung region during expiration.
Due to the high diffusion capacity of alveolar NO into blood and the sensitivity of the capillary smooth muscle tone to the vasodilatory effect of NO, the NO has a rapid effect on the smooth muscle. Even the short period at the end of inspiration when the last alveoli will be opened before recollapse or bronchial reclosure at the beginning of expiration may be enough to dilate the capillaries. In the collapsed alveoli, the perfusion so enhanced does not participate in the gas exchange. The capillaries around the alveoli remaining open throughout the expiration will also dilate due to the inhaled NO. If the increased oxygenation in the latter is enough to overcome the ineffective dilatation around the collapsed alveoli a positive net oxygenation improvement will be obtained.
The current invention relates to a method for improving oxygenation in subjects having essentially healthy lungs, as evidenced by the absence of a diagnosis of lung disease or injury, but having reduced alveolar gas exchange area. This reduction may be caused by such acute circumstances as an unnatural body position, or may be, for example, chronic as caused by obesity. The method employs the administration of nitric oxide into the breathing gases of such subjects. NO provided to alveoli collapsing during expiration is small compared to those remaining open, thereby to provide net reduction in the shunt and thus an oxygenation improvement. This result may be gained either by precise control of the inspired NO concentration or by pulsed administration of the NO.
The inhalation NO delivery to the collapsing alveoli has to be small enough not to exert vasodilatation, whereas the delivery to the alveoli remaining open throughout inspiration and expiration has to be sufficient to create the dilatation. For an administration of NO taking place at constant inspired concentration, precise control of the delivery rate is required to limit the amount of NO delivered to collapsing lung areas yet to provide enough NO for the alveoli remaining open so as to get the net effect in the form of pulmonary shunt reduction and oxygenation improvement.
Alternatively, the pulse NO administration can be timed to occur in the first e.g. 30-70% of inspiration. Such administration avoids delivery into the last opening alveoli and thus dilatation of the capillaries associated with those alveoli. With pulsed administration, control of the NO delivery rate is less critical.